SA is one of the indispensable metabolites of energy cycle in all living organisms, both plant and animal. In animals, it also provides—in cooperation with orphan receptors—a number of signal functions.
The medicinal features of SA have been known since the 15th century and were first described in the pharmacopeia of an Armenian physician Amasiatsi in 1493 (see “Garbage for Ignoramus”, medieval encyclopedia, http:**libbox.info/book_reading—91900.html).
SA possesses a large number of features: it “catalytically” contributes to the activation of energy exchange and has a cardiotonic, radioprotective and mild diuretic effect.
However, experiments show that SA samples of “natural” (i.e., obtained from amber) and synthesized by various methods are not identical in their biological activity. Synthetic samples mainly have evident diuretic and, to some extent, energizing features. We have conducted a number of tests, which allow one a reliable determination of SA biological activity; among them are those that provide technological control over the production released. We have examined more than 150 samples obtained with a variety of techniques. Since there are no physical-chemical methods, which would allow one to reveal differences between samples, we have conducted and applied biological tests, that reliably measure biological activity.
Several methods of SA synthesis are known. They utilize different kinds of raw materials: first of all, maleic anhydride, maleic acid, butadiene rubbers, furfural, etc. As a rule, the authors of the patents below do not declare the level of SA biological activity.
A method of SA synthesis that “reveals various kinds of biological activity” (RU Patent No. 2236398) is based on the oxidation of furfural with hydrogen peroxide, with the further addition of an alkaline reagent at variable pH (from <4 to 7), followed by neutralization, evaporation and re-crystallization from acetone and water to purify the product from traces of maleic, fumaric and oxalic acids (Patent RU 2098804). With all the obvious technological complexity of the synthesis (a lot of stages and use of a flammable organic solvent, requiring special use conditions) and the necessity of an additional stage of re-crystallization, it is almost impossible to achieve the 90% product yield declared by authors. The biological activity of SA obtained by this method is limited: according to the tests conducted, this acid is mainly a diuretic. In addition, the method does not produce the substance that would meet food safety requirements: the product contains a lot of harmful impurities.
There are numerous methods of SA synthesis through the liquid-phase catalytic reduction of maleic anhydride (maleic acid) at increased temperature and pressure.
The catalysts used in the known methods of SA synthesis are group VIII metals (nickel, ruthenium, palladium, rhodium or platinum), being either in the form of skeletal contact or applied on various supports (activated carbon, alumina, kiesel-guhr, asbestos etc.)
A common shortcoming of all these methods is the use of contacts with a high content of precious metals and the low product yield per unit weight of active component.
Data on the biological activity of SA obtained with the above-mentioned methods are not available in the patents noted above.
In RU Patent No. 2129540, hydrogenation of maleic anhydride or maleic acid in water is performed in the presence of a palladium-containing supported catalyst, with a palladium-nickel or palladium-iron catalyzing contact. This method allows one to achieve a high yield of SA (up to 99.7%), along with high productivity and good quality (melting temperature, 186.8-187.0° C.; main substance content, up to 99.8%; no impurities, i.e., maleic or fumaric acid).
According to our tests, a shortcoming of this method is that the biological activity of the highly purified SA synthesized by hydrogenation differs from that of natural SA obtained by pyrolysis of amber crumb.
A method of synthesis of highly purified, biologically active SA by hydrogenation of maleic anhydride (maleic or fumaric acids) in the aqueous medium on a heterogeneous catalyst is known, whose active phase is a complex compound of palladium and iron with succinic, maleic or fumaric acids or their alkalic salts (RU Patent No. 2237056). The catalytic complexes are applied on a support at the moment of their formation. Succinic acid obtained by this method possesses biological properties similar to those of natural SA.
A shortcoming of this method is the necessity of a separate preliminary multi-stage procedure for synthesis of the catalyst, which includes:                preparation of 3-4 initial solutions;        slurrying of supporting material;        consecutive dosing of initial solutions under pH-monitoring;        incubation at certain temperatures after dosing of each initial solution;        filtration of catalyst suspension;        washing of catalyst on a filter;        drying of catalyst to a certain residual moisture.        
As a result of complexity of this procedure, one would encounter problems with the conversion of a laboratory setup to a production unit and with instability of biological activity of SA obtained on apparatus of different type (see the results of tests according to the technique described in example 13 RU Patent No. 2237056). Less than 60% of the laboratory-synthesized SA samples were biologically active. Among the industrially produced samples, which were synthesized according to the procedure described above, only 12% of batches had appropriate values of biological activity.
The objective of the proposed method is to simplify the method of SA synthesis, so that the product would be of high purity and, at the same time, possess a stable high biological and adaptogenic activity.
This objective is achieved by (1) elimination of the separate stage of catalyst synthesis with its preliminary separation, (2) improvement (simplification) of the procedure of obtaining the hydrogenation catalyst, and (3) application of a seed on the stage of crystallization, which should be SA with high biological activity.
In one aspect, a method for preparing the succinic acid with a stably high biological and adaptogenic activity, includes the stages of producing a modified palladium-containing catalyst by using an acid and liquid-phase hydrogenation of unsaturated acid compounds on the said modified catalyst at an increased temperature and pressure, with further separation of the catalyst and the succinic acid, where the modification is performed over a prefabricated palladium-containing catalyst covering a carrier, in an oxygen-free atmosphere, in an aqueous medium of succinic, maleic or fumaric acids and/or their mixtures at the Pd2+/acid ratio of 1:1-1:100; thereupon, the process of liquid-phase hydrogenation of unsaturated acid compounds selected from maleic, fumaric acids or their anhydrides or their mixtures, is performed, and the product resulted from the hydrogenation process is obtained by crystallization from the aqueous solution containing 0.001-0.01 wt. % seed represented by the succinic acid with high biological activity.
The conducted experiments showed that a catalyst with desirable features (active and selective towards hydrogenation of maleic anhydride and maleic/fumaric acids into highly bioactive SA) can be obtained by preliminary (right before hydrogenation) modification of any palladium-containing supported catalyst with maleic, fumaric or succinic acids.
The modification of palladium catalysts with the aforementioned acids is conducted in aqueous solutions of these acids in an oxygen-free atmosphere. The concentration of the catalyst suspension in the aqueous solution and the palladium/acid ratio are maintained within the range of 0.1-1.5 wt. % and 1:1-1:100 respectively. It is possible to use a higher acid/palladium ratio; however, this will result not only in the absence of any extra positive effect but also in the danger of palladium being transferred from the catalyst surface into the solution, this decreasing the catalyst activity. The concentration of supported palladium can be altered within 0.1-1.0 wt. %, with the concentration of acids-modifiers varying within 0.01-0.7%—depending on the concentration of supported palladium and the chosen palladium/acid ratio. The duration of modification was 0.5-2 hours.
The process of modification can be carried out right in the hydrogenation reactor, under an oxygen-free atmosphere, with constant stirring, and within a wide range of temperatures: 5-70° C. (preferably, 15-40° C.).
After the process of modification is finished, the reactor is loaded with maleic anhydride (maleic or fumaric acids), and the system is purged with hydrogen, this followed by setting the necessary temperature condition and hydrogen pressure. The process goes at temperature 100-120° C. and pressure not more than 25 atm. A higher pressure does not give an additional positive effect. After the hydrogen consumption is finished, and the reaction mixture having been incubated for some time, the catalyst is separated by “hot” filtration, followed by feeding the catalyst (aqueous solution of succinic acid with a temperature 80-100° C.) into a heated crystallizing tank, previously supplied with a so-called “seed”, an etalon acid of natural origin or equally bioactive. The crystallization is performed in a regime of regulated temperature lowering: first at a rate 3-4°/min (up to 45° C.), then 1-2°/min (to 25° C.), and finally 0.3-0.5°/min (to 5-15° C.). This procedure yields a fine-crystalline precipitate of SA, which is then filtered and dried at a temperature not more than 100° C.
The SA obtained according to this procedure (after separation of source solution and drying) has a high purity (main substance content, not less than 99.0%; no maleic and fumaric acids) and does not differ in biological activity from the acid used as the “seed” of crystallization.
The advantages of the proposed method are obvious: its implementation would substantially simplify the entire technological process of SA synthesis (including the synthesis of catalyst) and also reduce its cost. Tests have shown that the SA produced by this method is characterized by a high biological activity—as high as that of the prototype and even higher in some cases. A peculiar feature of the SA obtained by the method proposed is the stability of its biological activity, whose parameters are independent of the scale of industrial production. The high bioactivity has been confirmed by testing samples according to the technique by example 13. The tests has shown requirements compliance of samples in 92% of cases—independently of the production scale (laboratory or industrial).
The proposed method also allows one to implement the production process with a wide range of modern supported catalysts, which have palladium as their active phase.
Implementation of the technique is illustrated by the examples given below. Examples 1, 2 and 3 show data for conventional analog and the conventional prototype. Examples 4-10 illustrate the invention. We used “natural” SA obtained by pyrolysis of amber crumb as a control. Examples 11-14 present the results of testing samples 1-10 for bioactivity, with the “natural” SA used as a control.